More than 400 distinct arthropod-borne viruses (arboviruses) are currently characterized and available at the Yale Arbovirus Research Unit. About 70 of these are known to cause significant disease of man. The majority belong to the families: Togaviridae, Bunyaviridae, Rhabdoviridae, and Reoviridae (orbiviruses). Among these diseases are yellow fever, Venezuelan encephalitis, Colorado tick fever, and several other fevers, hemorrhagic fevers, and encephalitides. In spite of vaccination, yellow fever still breaks out periodically in the Americas and Africa, and numerous properties of arboviruses and their vectors, including virulence, ecology in tropical ecosystems, over-wintering, vector competence, structure-function relationships, and pathogenesis need further study. The central unifying theme of this proposal is the application of genetically defined properties of both vectors and viruses to find means to control and prevent infection of man. The projects involve studies in four separate but inter-related areas in which intervention is possible: vector competence, virus persistence in tropical ecosystems, virus structure-function relationships, and virus virulence at the cell level. The projects were chosen for their intrinsic importance as well as for their value as models. Project #1 uses yellow fever and orbiviruses in genetically defined vectors to determine vector competence, pathogenesis, and interseasonal virus persistence. Project #2 investigates mechanisms of persistence of virus with vectors and vertebrates in the tropical ecosystem uniquely available in Panama. In Project #3 orbivirus genes which have been characterized at Yale by PAGE analysis will be related to structure, function, and geographic ecologic variation using the wide assortment of orbivirus strains in collections at Yale and Gorgas Laboratories. Project #4 probes the mechanisms of infection at the virus-cell level and the effect of substances such as neurotransmitters applied to prevent or alter attachment.